Destruction of WiDr multicellular tumor spheroids with the novel thymidylate synthase inhibitor 1843U89 at physiological thymidine concentrations

• Published in: Cancer chemotherapy and pharmacology Vol. 33; no. 6; pp. 455 - 459
• Main Authors: BANKS, S. D, WATERS, K. A, BARRETT, L. L, DICKERSON, S, PENDERGAST, W, SMITH, G. K
• Format: Journal Article
• Language: English
• Published: Berlin Springer 1994
• Subjects: Antineoplastic agents; Antineoplastic Agents - pharmacology; Biological and medical sciences; Carcinoma - blood; Carcinoma - drug therapy; Cell Division - drug effects; Colonic Neoplasms - blood; Colonic Neoplasms - drug therapy; General aspects; Humans; Indoles - pharmacology; Isoindoles; Medical sciences; Methotrexate - pharmacology; Pharmacology. Drug treatments; Quinazolines - pharmacology; Thymidine - blood; Thymidylate Synthase - antagonists & inhibitors; Time Factors; Tumor Cells, Cultured; Human; Cell culture; Solid tumor; Enzyme; Transferases; Enzyme inhibitor; Cytotoxicity; Spheroid; Malignant tumor; Thymidylate synthase; In vitro; Methyltransferases; Established cell line; Digestive diseases; Intestinal disease; Colon; Tumor cell
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/BF00686500

The activity of a novel thymidylate synthase inhibitor, 1843U89, against WiDr human colon carcinoma multicellular tumor spheroids was investigated. Continuous exposure of the spheroids to 3 nM 1843U89 for 10 days resulted in spheroid disruption, whereas 100 nM methotrexate (MTX) was required for similar effects. Short-term treatment experiments demonstrated that a 3-day exposure to 100 nM 1843U89 caused spheroid disruption 9 days after drug removal. A 4-day exposure to 10 nM 1843U89 caused spheroid disruption 8 days after drug removal. In contrast, treatment with 10 or 100 nM 1843U89 for 6-48 h or treatment with 1 nM 1843U89 for up to 5 days caused only growth delay. Continuous exposure of spheroids to 30 nM 1843U89 in the presence of 0.05-0.3 microM thymidine was as effective in causing spheroid disruption as treatment in the absence of thymidine, but treatment in the presence of 0.7-3.0 microM thymidine caused partial reversal of spheroid disruption. The results of these experiments suggest that 1843U89 should have potent solid tumor activity in humans but should be less effective in mice due to differences in circulating thymidine levels (0.1 vs 1 microM, respectively).